VEGFR2 Trafficking, Signaling and Proteolysis is Regulated by the Ubiquitin Isopeptidase USP8

• Published in: Traffic (Copenhagen, Denmark) Vol. 17; no. 1; pp. 53 - 65
• Main Authors: Smith, Gina A., Fearnley, Gareth W., Abdul‐Zani, Izma, Wheatcroft, Stephen B., Tomlinson, Darren C., Harrison, Michael A., Ponnambalam, Sreenivasan
• Format: Journal Article
• Language: English
• Published: Former Munksgaard John Wiley & Sons A/S 01.01.2016; Wiley Subscription Services, Inc
• Subjects: de‐ubiquitination; Endopeptidases - metabolism; Endosomal Sorting Complexes Required for Transport - metabolism; Endosomes - metabolism; Human Umbilical Vein Endothelial Cells - metabolism; Humans; Original; Protein Transport; Proteolysis; Signal Transduction; trafficking; Ubiquitin Thiolesterase - metabolism; Ubiquitination; USP8; Vascular endothelial growth factor; Vascular Endothelial Growth Factor Receptor-2 - metabolism; VEGFR2; VEGF‐A; VEGFR2; USP8; signal transduction; de-ubiquitination; VEGF-A; trafficking; proteolysis
• ISSN: 1398-9219; 1600-0854
• DOI: 10.1111/tra.12341

Vascular endothelial growth factor A (VEGF‐A) regulates many aspects of vascular function. VEGF‐A binding to vascular endothelial growth factor receptor 2 (VEGFR2) stimulates endothelial signal transduction and regulates multiple cellular responses. Activated VEGFR2 undergoes ubiquitination but the enzymes that regulate this post‐translational modification are unclear. In this study, the de‐ubiquitinating enzyme, USP8, is shown to regulate VEGFR2 trafficking, de‐ubiquitination, proteolysis and signal transduction. USP8‐depleted endothelial cells displayed altered VEGFR2 ubiquitination and production of a unique VEGFR2 extracellular domain proteolytic fragment caused by VEGFR2 accumulation in the endosome–lysosome system. In addition, perturbed VEGFR2 trafficking impaired VEGF‐A‐stimulated signal transduction in USP8‐depleted cells. Thus, regulation of VEGFR2 ubiquitination and de‐ubiquitination has important consequences for the endothelial cell response and vascular physiology. Endothelial cells regulate many aspects of vascular physiology including blood pressure, vascular repair and new blood vessel sprouting. Binding of vascular endothelial growth factor A to a receptor tyrosine kinase (vascular endothelial growth factor receptor 2, VEGFR2) stimulates intracellular signaling and the endothelial response. We show that the ubiquitin isopeptidase, USP8, is essential for VEGFR2 trafficking, de‐ubiquitination, signal transduction and proteolysis. Biochemical pathways that control the ubiquitination and de‐ubiquitination of VEGFR2 thus regulate endothelial decision‐making processes that influence vascular physiology.